Use of human growth hormone for preoperative administration

ABSTRACT

The invention relates to the use of growth hormone (GH) or effective analogues thereof for the manufacture of a medicament intended for preoperative administration in order to reduce protein loss, especially for the manufacture of a medicament for the preparation of a patient for surgery or other elective situation where catabolism may be induced.

The present invention relates to the use of growth hormone (GH) oreffective analogues thereof for the manufacture of a medicament intendedfor preoperative administration in order to reduce protein loss and forthe preparation of patients for surgery so as to achieve an improvedoutcome.

INTRODUCTION

Growth hormone (GH) is a peptide present in plasma. It is a 191 aminoacid peptide secreted into the blood stream. It acts on receptors in theliver, muscle, fat, growth plate and in other tissues. Its actions onskeletal growth and on protein anabolism are mediated at least in largepart by insulin-like growth factor-1 (IGF-1). IGF-1 is released by theliver into the blood stream in response to stimulation by GH. It is alsoproduced in tissues including muscle in response to the action of GH.Human GH has been purified from human tissues and the complete aminoacid sequences established. GH is found in other species includingruminants with extensive homologies to those in humans. Because GH canonly be purified from the human pituitary gland it is scarce: furtherpurified GH is considered unsafe because of the risk of contamination byprions.

Nowadays large scale production for both hormones is readily achievedusing recombinant DNA techniques. It has been demonstrated thatrecombinant GH (rGH) stimulates skeletal growth in GH deficiency andthat it reduces protein catabolism in patients with severe catabolicillness consequence on surgery or burns. These effects of GH are due toa reduction in protein breakdown and possibly an increase in proteinsynthesis. Moreover these actions of GH are associated with a rise inserum IGF-1 levels.

In EP 288 478, Brigham and Women's hospital, the use of growth hormonetogether with a hypocaloric dietary component is disclosed for producingor maintaning a positive nitrogen balance. The protein builtup isthereby maintained.

WO 91/11195, Novo Nordisk, discloses the use of growth hormone forreducing the incidence of post-surgical problems, wherein the hormone isadministered for a period starting at the time of an operation.

However, all consideration of the use of GH to ameliorate a catabolicstate has been restricted to its use after a state of catabolism exists.Prior art does not exist to suggest an alternate use or approach or thatthe use of GH prior to an insult would be of therapeutic value.

THE INVENTION

We have found that a specific biological action of GH and its analogues,when administered to mammals including man for a period prior to theinduction of a catabolic state reduces the severity of the catabolicstate.

We have also found that prophylactic use of GH or effective analoguesacts to allow parenteral nutritional therapy to be effective in acatabolic state in a manner not seen if GH is administered solely afterthe catabolism has been established. Thus GH or affective analogues are,according to the present invention, suitable preparative therapies forhuman subjects facing elective surgery or other comparable catabolicstresses.

The use is especially of interest for the preparation of a patient formajor surgery of an elective nature including major cardiac surgery,major abdominal surgery, orthopaedic surgery, neurosurgery, or any othersurgical procedure of an elective nature. A universal problem of majorsurgery is that catabolic states develop after surgery which prolong thepatients convalescence and increase the risk of death or morbidity fromcardiac, respiratory or infective complication and slow the rate ofwound healing. The invention discloses the considerable advantage to thepatient placed electively in that position if prepared for a periodprior to the surgery with GH or its effective analogue to both reducethe severity of the catabolic state and/or improve the capacity of thepatient to respond to current therapeutic modalities which arenutritional support and/or GH administration.

The invention thus relates to the use of growth hormone (GH) oreffective analogues thereof for the manufacture of a medicament intendedfor preoperative administration in order to reduce protein loss and thusfor improvement in outcome following surgery.

Normally this applies in the preparation of a patient for surgery orother elective situation where catabolism may be induced in order toreduce the severity of a postoperative catabolic state.

It also relates to the use for the manufacture of a medicament forpreoperative and postoperative administration for the preparation of apatient for surgery or other elective situation where catabolism may beinduced, i.e. that GH is given prior to surgery and thereaftercontinously after surgery.

The surgery includes abdominal, cardiac, thoracic, neuro or orthopaedicsurgery.

Preferably human GH is used and the dose administered could be 0.1 to 1mg/kg/day preferably 0.1 to 0.4 mg/kg/day.

The invention also relates to the method of treatment of patients in thesituations as given above.

The administration of GH could be subcutaneous, intramuscular,intravenous, intranasal, oral or dermal or a combination of theseroutes. And the hormone is administered for at least 12 hours and up to365 days and preferably for 3 to 60 days.

This claimed use of GH prior to surgery enhances the efficacy ofhormonal, pharmaceutical or nutritional management of a postoperativecatabolic state.

The hormone may be used in association with other nutritional,pharmaceutical or hormonal therapies pre- and/or post surgical.

The capacity of patients to maintain metabolic status duringinvestigations that require the withdrawal of food (for example bowelbiopsy, radiological investigation) could be improved.

DETAILED DESCRIPTION OF THE INVENTION

The following figures are included:

FIG. 1. Plasma IGF-I concentration during growth hormone treatment

FIG. 2. The percentage change in net protein catabolism (NPC) duringtotal parenteral nutrition (TPN).

The preferred form of the invention will now be described with referenceto the following non-limiting examples.

EXAMPLE 1

Fully weaned cryptorchid ram lambs weighing 15 to 20 kg were used. Theanimals received once daily injections of saline (n=3) or recombinantbovine GH (n=4). Bovine GH is fully biologically active in sheep, ofequal potency to ovine GH, but is the only ruminant form available asrecombinant derived hormone. The bovine GH was donated by Dr I. Hart ofAmerican Cyanamid, Princeton N.J. For the first 5 days of treatment theywere feed ad libitum. For the next two days they were starved to inducea catabolic state. Following 48 hours of starvation the animals wereplaced in slings and intravenous catheters inserted for the infusion ofparenteral nutrition and the study of net protein catabolism.

FIG. 1 shows plasma IGF-1 levels through the first two phases of theexperiment. It shows that pretreatment bovine GH elevated plasma IGF-1with reference to the control group both before and during starvation.Whereas in starvation in the saline group IGF-1 fell with reference tobaseline, in the GH treated group IGF-1 levels remained above basallevels. (*=p<0.05 with respect to the equivalent control value;BGH=bovine growth hormone).

Commencing at 48 hours into starvation the animals received a constantinfusion of parenteral nutrition for 12 hours comprising a balancedamino acid solution (synthamin 17, Travenol) at 1.5 g/kg/day. Nonprotein calories were provided as a 50:50 mix of dextrose and intralipid20 (Kabi Pharmacia) at 20 kcal/kg/day. 4 hours after commencing theparenteral nutrition, a primed constant infusion of both stable andradioisotopes was commenced. Isotopic steady state was reached 3 hourslater. The isotopic infusion was of N¹⁵ urea infused at a rate of 10ug/kg.min after a priming dose of 4.5 mg/kg. The technique is aspublished and enables calculation of net protein catabolism from themeasurement of urea production. At the same time C¹⁴ leucine was infusedat 7.5 nCi/kg/min following a 60.1 leucine prime as describedpreviously. This enables calculation of whole body protein catabolism--ameasure of absolute protein catabolic rate.

The net protein catabolism (NPC) at the point of first measurement wasless (p<0.01) in the GH treated group than in the saline group(2.4±(SEM)0.2 g/kg/day versus 3.2 gm/kg/day). Further whereas in thesaline treated group the animals continued to become more catabolic(p<0.05) despite the 5 hours further parenteral nutrition, in the GHtreated group, the rate of protein catabolism decreased (p<0.05) duringthis period (FIG. 2). (BGH=bovine growth hormone).

The rate of whole body protein catabolism was calculated from theleucine production rate. After 7 hours of parenteral nutrition the wholebody catabolic rate was decreased (p<0.05) in the GH treated group(10.89±0.34 g/kg/day) compared to the saline group (12.87±0.67g/kg/day).

This experiment shows that 5 days of treatment with GH commencing priorto the imposition of a catabolic stress elevates IGF-1 levels which aremaintained at higher levels during the period of catabolism. Furtherwith the continuation of the GH into the starvation period there was anunequivocal reduction in both whole body and net protein catabolism.Further whereas nutritional therapy did not alone reverse the catabolicstate, when combined with GH which commenced prior to the catabolicillness, it did so.

Because this experiment does not unequivocally separate GH therapy givenprior to the imposition of the stress from that given after, theexperiment in example 2 was performed using human GH.

EXAMPLE 2

20 kg cryptorchid lambs were acclimatised to laboratory conditions. Theywere treated for 7 days with recombinant human GH (Kabi Pharmacia) orplacebo at a dose of 0.5 mg/kg body weight and day divided into twodoses subcutaneously. The lambs were then starved for 48 hours to mimica catabolic stress. During the 48 hours of catabolism they were eithertreated with placebo or human GH at a dosing regime comparable to thatused in the precatabolism phase. After 48 hours the lambs were placed inslings, percutaneously catheters were inserted in the jugular veins anda primed isotopic infusion of C¹⁴ -urea commenced at a rate of 1.8nCi/kg/min 450:1 priming dose. Isotopic steady state was achieved after3 hours and urea turnover rate was calculated after 5 hours furtherinfusion. From urea turnover, net protein catabolism was calculatedmathematically as described previously (Shaw J. H. F., Wolfe R. R.Glucose, fatty acid and urea kinetics in patients with severepancreatitis. Ann. Surg. 204, 665-672, 1986). Table 1 describes theresults of the study.

                  TABLE 1                                                         ______________________________________                                                                during   net protein                                              Precatabolism                                                                             catabolism                                                                             catabolism                                   Group number                                                                              therapy     therapy  g/kg/day                                     ______________________________________                                        A 4         placebo     placebo  2.59 ± 0.07                               B 3         placebo     hGH      2.76 ± 0.43                               C 3         hGH         placebo  2.75 ± 0.10                               D 3         hGH         hGH       1.92 ± 0.12*                             ______________________________________                                    

Data are expressed in table 1 as mean±SEM. *p<0.02 versus other groups

This example shows that hGH given prior to a catabolic stress in sheetsacts synergistically with post catabolic management to reduce netprotein catabolism.

EXAMPLE 3

20 kg cryptorchid lambs were acclimatised to laboratory conditions. Theywere treated for four days with recombinant bGH or placebo (saline) at adose of 0.3 mg/kg body weight daily divided in two doses per day, i.e.eight injections before starvation. The lambs were starved during 70hours and were given six injections (both saline and bGH) afterinitiating starvation. Net protein catabolism (NCC) was measured by Ureaturnover and calculated as described in example 2. Table 2 gives theresults of the study.

                  TABLE 2                                                         ______________________________________                                                                during   net protein                                              Precatabolism                                                                             catabolism                                                                             catabolism                                   Group number                                                                              therapy     therapy  g/kg/day                                     ______________________________________                                        I           placebo     placebo  3.37 ± 0.78                               II          placebo     bGH      2,16 ± 0.34*                              III         bGH         placebo  2.21 ± 0,41*                              IV          bGH         hGH      2.03 ± 0.54*                              ______________________________________                                    

Data are expressed in table 1 as mean±SEM. *p<0.001 versusplacebo-placebo

Conclusion

The conclusion is apparent from these examples that the administrationof GH prior to a catabolic stress is associated with an elevation inplasma IGF-1, is associated with reduced catabolism during the period ofstress, is associated with a synergism with nutritional management ofthe catabolic stress. Thus it is clear that the prophylactic use of GHor its effective analogue including IGF-1 or its effective analogue willreduce the degree of catabolism present after a stress such as surgeryand will act synergistically with the possible therapeutic approachesnow available to management catabolic illness.

Finally it has to be understood that various other modifications and/oralterations may be made without departing from the spirit of the presentinvention as outlined herein.

I claim:
 1. Method for preoperative treatment of patients in need of reduction of protein loss by administration of an effective amount of hormone (GH).
 2. Method according to claim 1 for the preparation of a patient for surgery or other elective situation where catabolism may be induced.
 3. Method according to claim 1 for the preparation of a patient for surgery or other elective situation to reduce the severity of a postoperative catabolic state.
 4. Method according to claim 1 for preoperative and postoperative administration for the preparation of a patient for surgery or other elective situation where catabolism may be induced.
 5. Method according to claim 1 for reducing the severity of catabolism following surgery.
 6. Method according to claim 1 for improvement in outcome following surgery.
 7. Method according to claim 1 in which human GH is used.
 8. Method according to claim 1 in which the dose administered is 0.1 to 1 mg/kg/day.
 9. The method of claim 5 wherein said surgery is selected from the group consisting of abdominal, cardiac, thoracic, neuro and orthopaedic surgery.
 10. The method of claim 8 wherein said dose is 0.1 to 0.4 mg/kg/day.
 11. The method of claim 1 wherein said administration is for at least 12 hours.
 12. The method of claim 1 wherein said administration is for 3 to 60 days.
 13. Method according to claim 8 in which human GH is used.
 14. Method according to claim 10 in which human GH is used.
 15. Method according to claim 11 in which human GH is used.
 16. Method according to claim 12 in which human GH is used.
 17. Method according to claim 2 in which human GH is used.
 18. Method according to claim 3 in which human GH is used.
 19. Method according to claim 4 in which human GH is used.
 20. Method according to claim 5 in which human GH is used. 